ATR promotes mTORC1 activity via de novo cholesterol synthesis.

Autor:	Tangudu NK; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Grumet AN; Center for Advanced Biotechnology and Medicine, Department of Pharmacology, and Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ., Fang R; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Buj R; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Cole AR; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Uboveja A; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Amalric A; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Yang B; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.; Tsinghua University School of Medicine, Beijing, P.R. China., Huang Z; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA., Happe C; Health Sciences Mass Spectrometry Core, University of Pittsburgh School of Medicine, PA., Sun M; Health Sciences Mass Spectrometry Core, University of Pittsburgh School of Medicine, PA., Gelhaus SL; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; Health Sciences Mass Spectrometry Core, University of Pittsburgh School of Medicine, PA., MacDonald ML; Health Sciences Mass Spectrometry Core, University of Pittsburgh School of Medicine, PA.; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Hempel N; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.; Division of Malignant Hematology & Medical Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA., Snyder NW; Department of Cardiovascular Sciences, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA., Kedziora KM; Department of Cell Biology, Center for Biologic Imaging (CBI), University of Pittsburgh, Pittsburgh, PA., Valvezan AJ; Center for Advanced Biotechnology and Medicine, Department of Pharmacology, and Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ., Aird KM; Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.; UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 24. Date of Electronic Publication: 2024 Oct 24.
DOI:	10.1101/2023.10.27.564195
Abstrakt:	DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found have increased ATR activity. Mechanistically, we found that ATR promotes de novo cholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular contexts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism. Competing Interests: Declaration of Interests All authors declare no competing interests.
Databáze:	MEDLINE
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